Compositions in the form of solid solutions

ABSTRACT

Compositions in the form of solid solutions containing 
     a) 1-90% by weight of a coumarin derivative A from the group of alkoxycoumarins with a heterocyclic substituent or of hydroxycoumarins esterified with a sulfonic acid as active substance and 
     b) 10-99% by weight of at least one water-soluble polymer B as carrier substance.

The present invention relates to novel compositions in the form of solidsolutions, containing

a) 1-90% by weight of a coumarin derivative A from the group ofalkoxycoumarins with a heterocyclic substituent or of hydroxycoumarinsesterified with a sulfonic acid as active substance and

b) 10-99% by weight of at least one water-soluble polymer B as carriersubstance.

The invention additionally relates to a process for the production ofthese compositions and to their use as drugs.

Compositions in which the active substance is present homogeneouslydispersed in a water-soluble polymer are generally known in numerousembodiments. For example, EP-A 240 773, EP-A 462 066, EP 521 310 andDrug Development and Industrial Pharmacy, 6 (2) (1980) 137-160 describecompositions containing hydroxypropylmethylcellulose orpolyvinylpyrrolidone as carrier substance.

Alkoxycoumarins with a heterocyclic substituent ##STR1## R^(I), R^(II),R^(III), R^(IV) =substituents Het=N, S and O containing heterocyclicradical and sulfonic esters of hydroxycoumarins ##STR2## R^(I), R^(II),R^(III) =Substituents

as well as pharmaceutical compositions containing these substances asactive substances are known and are proposed in U.S. Pat. No. 5,073,563for the treatment of disorders of the central nervous system, especiallyof neurodegenerative disorders and parkinsonism, and in EP-B 111 746 forthe treatment of psychological disturbances, especially of depressions.The disadvantage of these active substances and their pharmaceuticalcompositions described therein is that they are unsatisfactory inrespect of their bioavailability because of their low solubility inwater. It is therefore possible for these coumarin derivatives which arein crystalline form to be absorbed only very slowly and incompletelyafter intake.

It is an object of the present invention to provide compositions in theform of solid solutions with good solubility and bioavailability as wellas rapid absorption of the coumarin derivatives A.

We have found that this object is achieved by the compositions definedat the outset.

The invention furthermore relates to a process for their production,their use as drugs and their dosage forms.

The compositions according to the invention contain

a) 1-90% by weight, preferably 10-40% by weight, of a coumarinderivative A from the group of alkoxycoumarins with a heterocyclicsubstituent or hydroxycoumarins esterified with a sulfonic acid asactive substance and

b) 10-99% by weight, preferably 60-90% by weight, of at least onewater-soluble polymer B as carrier substance.

Suitable alkoxycoumarins A' with a heterocyclic substituent are thecompounds specified in U.S. Pat. No. 5,073,563, and those which arepreferably suitable here have a thiadiazole residue as heterocyclicsubstituent and are claimed in the cited publication. Particularlysuitable are

4-Trifluoromethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)methoxycoumarin

3,4-Dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)methoxycoumarin

3,6-Dichloro-4-methyl-7-(2-cyclopropylthiazol-4-yl)methoxycoumarin

3,4-Dimethyl-7-(2-methylthiazol-4-yl)methoxycoumarin

3,4-Dimethyl-7-(2-phenylthiazol-4-yl)methoxycoumarin

3,4-Dimethyl-7-(2-benzylthiazol-4-yl)methoxycoumarin

3,4-Dimethyl-7-(2-isopropylthiazol-4-yl)methoxycoumarin

3,4-Dimethyl-7-(2-cyclopropylthiazol-4-yl)methoxycoumarin

3,6-Dichloro-4-methyl-7-(2-isopropylthiazol-4-yl)methoxycoumarin

6-Bromo-3-chloro-4-methyl-7-(2-isopropylthiazol-4-yl)methoxycoumarin

Suitable hydroxycoumarins A" esterified with sulfonic acid are thecompounds described in EP-B 111 746.

The principle according to the invention is very particularly suitablefor compositions with3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)methoxycoumarin A'/1##STR3## from the group of alkoxycoumarins A' with a heterocyclicsubstituent, and with 7-hydroxy-3,4-dimethylcoumarin ethanesulfonicester A"/1 ##STR4## from the group of hydroxycoumarins A" esterifiedwith sulfonic acid as active substance.

The following water-soluble polymers B may be mentioned:

alkylcelluloses such as methylcellulose

hydroxyalkylcelluloses such as hydroxymethyl-, hydroxyethyl-,hydroxypropyl- and hydroxybutylcellulose

hydroxyalkylalkylcelluloses such as hydroxyethylmethyl- andhydroxypropylmethylcellulose

carboxyalkylcelluloses such as carboxymethylcelluloses

alkali metal salts of carboxyalkylcelluloses such as sodiumcarboxymethylcellulose

carboxyalkylcellulose esters

N-vinylpyrrolidone/vinyl acetate copolymers

polyvinylpyrrolidone

polyvinyl alcohol

polyacrylic acid and its salts

polymethacrylic acid and its salts

polyalkylene oxides such as polyethylene oxide and polypropylene oxideas well as copolymers of ethylene oxide and propylene oxide

polysaccharides such as alginic acid, its alkali metal and ammoniumsalts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic,guar gum and xanthan gum

chitin derivatives such as chitosan

pectins such as sodium carboxymethylamylpectin

starches

and mixtures of these water-soluble polymers.

Preferred polymers B are methylcelluloses,hydroxypropylmethylcelluloses, hydroxypropylcellulose,polyvinylpyrrolidone and N-vinylpyrrolidone/vinyl acetate copolymers,especially polyvinylpyrrolidone and copolymers of 40-70% by weight ofN-vinylpyrrolidone and 30-60% by weight of vinyl acetate.

The term water-soluble means that at least 0.5 g, preferably 2 g, of thepolymer dissolve, possibly colloidally or with gel formation, in 100 gof water at 20° C.

A solid solution is present when the active substance is essentially inthe form of a molecular dispersion in the polymer matrix (J. Pharm. Sci.60 (1971) 1281-1302).

The compositions according to the invention can be produced by eithermelting the coumarin derivative A directly in the form of a physicalmixture with the polymer B or mixing it with the polymer melt which hasalready been prepared.

Otherwise, mixing of the coumarin derivative A with the melt takes placein a conventional manner in extruders, preferably in single or twinscrew extruders at a temperature in the range from 50° to 200° C. Theshaping of the polymer melt which contains the coumarin derivative A togive the compositions according to the invention can take place, forexample, by calendering the extrudate by the method described in EP-A240 906 and by the processing method disclosed in DE-A 38 30 355 bycomminuting the extrudate with rotating knives to pieces which are ofequal volume and have a solidified surface but are still deformable andsubsequently compressing to tablets in conventional tabletting machines.

The mixing of the active substance with the melt can also be carried outin other equipment suitable for this purpose and conventionally used toprocess plastics, e.g. calenders and injection molds.

The compositions according to the invention can also be produced bymixing the coumarin derivative A dissolved in a volatile solvent withthe polymer melt. It is furthermore possible to obtain a mixture ofcoumarin derivative A and polymer B by dissolving them together in avolatile solvent and subsequently evaporating off the solvent. Thecooled residue is further processed to solid dosage forms with shapingin conventional equipment as for the melt.

In some cases it may be expedient for the shaping to be preceded byapplication of the mixture of A and B, both in the form of the melt andin the form of a solution, for example onto a finely divided porouscarrier material such as silica gel, and by formation of inclusioncompounds e.g. with cyclodextrins and their derivatives.

It is additionally possible for the compositions according to theinvention to contain conventional pharmaceutical ancillary substancessuch as fillers, lubricants, release agents, flow regulators,plasticizers, dyes and stabilizers in amounts of up to about 60% byweight. These amounts and others indicated hereinafter are in each casebased on the total weight of the composition (=100%).

Examples of fillers which may be mentioned are the oxides of magnesium,aluminum, silicon and titanium as well lactose, mannitol, sorbitol,xylitol, pentaerythritol and its derivatives, with the amount of fillerbeing about 0.02-50, preferably 0.2-20% by weight.

Examples of flow regulators which may be mentioned are the mono-, di-and triglycerides of long-chain fatty acids such as C₁₂ -, C₁₄ -, C₁₆ -and C₁₈ -fatty acid, waxes such as carnauba wax and the lecithins, withthe amount being about 0.1-30, preferably 0.1-5, % by weight.

Examples of plasticizers which may be mentioned besides low molecularweight polyalkylene oxides such as polyethylene glycol, polypropyleneglycol and polyethylene/propylene glycol are polyhydric alcohols such aspropylene glycol, glycerol, pentaerythritol and sorbitol as well assodium diethyl sulfosuccinate, the mono-, di- and triacetate of glyceroland polyethylene glycol stearate. The amount of plasticizer is moreoverabout 0.5-15, preferably 0.5-5% by weight.

Examples of lubricants which may be mentioned are stearates of aluminumor calcium as well as talc and silicones, with the amount thereof beingabout 0.1-5, preferably 0.1-3% by weight.

Examples of stabilizers which may be mentioned are light stabilizers,antioxidants, radical scavengers and stabilizers against microbialattack, the amount thereof preferably being about 0.01-0.05% by weight.

It is possible to mix the ancillary substances into the melt or solutionof coumarin derivative A and polymer B. It is furthermore possible forthe ancillary substances to be incorporated together with the coumarinderivative A into the polymer melt or into the solution of polymer B. Inaddition, mixtures of ancillary substances, the coumarin derivative Aand the polymer B can be directly melted or dissolved together in asolvent. It is generally customary to melt a physical mixture ofancillary substances, coumarin derivative A and polymer B together.

The compositions according to the invention are used as drugs andemployed in the form of powders, granules, tablets, pellets,suppositories or in capsules or in injection solution.

For oral administration it is advisable to provide the compositions withcolored coatings, e.g. composed of titanium dioxide and of coloredpigments, to improve the appearance. Suitable for improving the tasteare coatings, for example glucose, sucrose, xylitol and mannitol.

The novel compositions in the form of solid solutions have advantagescompared with the prior art in that the release of the coumarinderivative A is better, with the result that its bioavailability andabsorption are considerably increased. The virtually homogeneousdistribution of the amorphous coumarin derivative A in the polymericcarrier substance B results in an improvement in the solubility comparedwith crystalline coumarin derivative A.

EXAMPLES 1 TO 9

The active substances used to produce the compositions according to theinvention were

A'/1 3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)-methoxycoumarinand

A"/1 7-hydroxy-3,4-dimethylcoumarin ethanesulfonic ester.

They were synthesized by the methods described in U.S. Pat. No.5,073,563 and EP-B 111 746 respectively.

The following commercially obtainable polymers B were used: (relativeviscosity determined by the ASTM D 2365-72 capillary method (EuropeanPharmacopoeia, vol. III, page 37))

B/1 copolymer of 60% by weight of N-vinylpyrrolidone (NVP) and 40% byweight of vinyl acetate; V=1.18-1.31 cps (1% solution in water, 25° C.)(Kollidon® VA64 from BASF AG)

B/2 Polyvinylpyrrolidone; V=1,430-1,585 cps (5% solution in water, 25°C.) (Kollidon® 17PF from BASF AG)

B/3 Polyvinylpyrrolidone; V=1.201-1.276 cps (1% solution in water, 25°C.) (Kollidon® 30 from BASF AG)

(V=viscosity)

The following substances were used as ancillary substances C:

C/1 Polyethylene oxide, M_(w) =6000 (Lutrol® E6000 from BASF AG)

C/2 Polyethylene oxide, M_(w) =1500 (Lutrol® E1500 from BASF AG)

C/3 Lactose monohydrate, finely powdered; complying with DAB, Ph Eur,BP, USP (from Meggle)

(M_(w) =weight average molecular weight)

The amounts of coumarin derivative A, of polymer B and, in some cases,of ancillary substance C indicated in Examples 1 to 6 and 9 were mixedand then introduced into a twin screw extruder and extruded through 5temperature zones from 60° to 130° C. The emerging polymer extrudate wasfed into a calender mutually opposite concave depressions in the rollershells and was shaped to 1000 mg tablets. Transparent yellow tabletswere obtained.

In Examples 1 to 6 release of active substance was measured by the USPXXI paddle method. This in vitro test method is used to determine therate of dissolution of shaped articles containing active substance (e.g.tablets).

To do this, 900 ml of 0.1N hydrochloric acid containing 0.05 mol/lsodium lauryl sulfate were equilibrated at 37° C. in a 1 l round-bottomvessel. During the test the 1000 mg tablet to be tested was located inthe center of the round bottom of the vessel below the paddle whichrotated at 100 rpm. After the test had lasted 1 hour in each case, theamount of released active substance was determined by UV spectroscopy.

The absolute bioavailability F was determined in Examples 7 to 9 bymeans of an in vivo test method.

The bioavailability (biological availability; F) of a drug means therate at which and the extent to which a therapeutically activeconstituent is released from a drug form, is absorbed and is finallyavailable at the site of action. The bioavailability on intravenousadministration is 100%.

The absolute bioavailability F is calculated using the followingequation: ##EQU1## AUC=area under the curve; area under theconcentration-time plot (plasma level plot)

AUC_(x) =area under the curve with any particular administration

AUC_(i).v. =area under the curve on intravenous administration

The in vivo test method entailed 1 tablet containing 300 mg of activesubstance being administered once to each dog (Beagle). Blood sampleswere taken at defined intervals for a period of 24 hours, and theconcentration of the active substance in the blood was determined.

Details of these tests and the results are to be found in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                         Ancillary                                                                           Release of                                              Coumarin derivative A                                                                   Polymer B                                                                           substance C                                                                         active substance                                                                        absolute                                 Example                                                                            % by weight                                                                             % by weight                                                                         % by weight                                                                         after 1 h** (%)                                                                         bioavailability F (%)                    __________________________________________________________________________    1    20   A"/1 80 B/1                                                                              --     6                                                 2    20   A"/1 80 B/2                                                                              --    77                                                 3    20   A"/1 60 B/1                                                                              20 C/1                                                                              37        not investigated                         4    20   A"/2 60 B/2                                                                              20 C/3                                                                              78                                                 5    19.5 A"/1 40.5                                                                             B/1                                                                              40 C/3                                                                              22                                                 6    20   A"/1 40 B/2                                                                              40 C/3                                                                              44                                                 7 (a)*                                                                             50   A'/1 --    50 C/3                                                                              --        1.00 (c)                                 8 (b)*                                                                             10   A'/1 --    90 C/2                                                                              --        0.17 (d)                                 9    10   A'/1 90 B/1                                                                              --    --        3.05 (d)                                 __________________________________________________________________________     (a) Trituration of A'/1 with lactose                                          (b) Melt embedding                                                            (c) F determined on one dog                                                   (d) Average of F determined on 4 dogs (calculated from the median)            *Comparative example                                                          **All forms reach 100% release of active substance after 8 h.            

EXAMPLE 10

In another example, the bioavailability of A"/1 in the compositionsaccording to the invention was measured. To do this, thepharmacokinetics of an extrudate composition (solid solution, activesubstance in amorphous form) were tested on dog (beagle). The plasmalevels achieved are indicated in Table 2. For comparison, the valuesreached with granules (active substance in ground but crystalline form)were also determined.

Composition of extrudate (tablet, about 1 g):

    ______________________________________                                        A"/1                 18.87% by weight                                         Vinylpyrrolidone/vinyl acetate                                                                     41.13% by weight                                         copolymer (60:40), (Kollidon ®                                            VA-64)                                                                        Lactose              40.00% by weight                                         ______________________________________                                    

Composition of granules (capsules, size 0):

    ______________________________________                                        A"1                   77.55% by weight                                        Lactose               11.64% by weight                                        Microcrystalline cellulose                                                                           7.75% by weight                                        Polyvinylpyrrolidone, K value 30                                                                     2.58% by weight                                        Mg stearate            0.48% by weight                                        ______________________________________                                    

The results are to be found in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Plasma levels of A"/1 (esuprone) in Beagle dogs -                             400 mg/kg of body weight of esuprone orally per day for 14 days                                Animal No. 3                                                                         Animal No. 4                                                                         Animal No. 5                                                                         Animal No. 6                                     Time after                                                                            400 mg/kg                                                                            400 mg/kg                                                                            400 mg/kg                                                                            400 mg/kg                                        administration                                                                        Granules                                                                             Granules                                                                             Extrudate                                                                            Extrudate                                         h!      ng/ml!                                                                               ng/ml!                                                                               ng/ml!                                                                               ng/ml!                                 __________________________________________________________________________    1st administration                                                                     before substance                                                                      *)     2.68   11.38  1.73                                             administration                                                                1       28.56  1.72   1245.92                                                                              2558.33                                          2       10.64  2.88   6907.77                                                                              8097.63                                          3       11.52  2.62   7307.85                                                                              12625.00                                         4       7.81   1.81   4653.01                                                                              5178.90                                          6       4.18   1.14   1011.11                                                                              1497.21                                          8       2.70   0.78   339.09 776.71                                           24      9.17   3.29   14.13  53.98                                   13th administration                                                                    24      7.16   9.31   17.87  54.34                                   14th administration                                                                    1       6.76   9.97   178.59 4795.10                                          2       16.48  0.66   263.98 12257.10                                         3       7.45   9.42   461.53 6466.05                                          4       4.70   7.15   542.59 3096.27                                          6       5.22   6.66   3503.58                                                                              1086.55                                          8       7.56   5.99   1242.95                                                                              714.03                                           24      1.63   3.33   7.48   36.62                                   __________________________________________________________________________     *) Value below the detection limit of 0.2  ng/ml                         

We claim:
 1. A solid oral dosable composition in the form of a solidsolution containinga) 1-90% by weight of a coumarin derivative A fromthe group of alkoxycoumarins with a heterocyclic substituent or ofhydroxycoumarins esterified with a sulfonic acid as active substance andb) 10-99% by weight of at least one water-soluble polymer B as carriersubstance.
 2. A composition as defined in claim 1, containinga) 10-40%by weight of the coumarin derivative A and b) 60-90% by weight of thewater-soluble polymer(s) B.
 3. A composition as defined in claim 1,containing3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)methoxycoumarin or7-hydroxy-3,4-dimethylcoumarin ethanesulfonic ester as coumarinderivative A.
 4. A composition as defined in claim 1, containingpolyvinylpyrrolidone and/or N-vinylpyrrolidone/vinyl acetate copolymersas polymer B.
 5. A drug comprising a composition as defined in claim 1in the form of powders, granules, tablets and pellets.
 6. A compositionas defined in claim 2, containing3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)methyoxycoumarin or7-hydroxy-3,4-dimethylcoumarin ethanesulfonic ester as coumarinderivative A.
 7. A composition as defined in claim 2, containingpolyvinylpyrrolidone and/or N-vinylpyrrolidone/vinyl acetate copolymersas polymer B.
 8. A composition as defined in claim 3, containingpolyvinylpyrrolidone and/or N-vinylpyrrolidone/vinyl acetate copolymersas polymer B.
 9. A process for producing a composition as defined inclaim 1, which comprises mixing the coumarin derivative A with polymer Bin a solvent, removing the solvent, and further processing the melt orthe residue remaining with shaping to particles.